The glutamate/glycine NMDA receptor has been implicated in a variety of central nervous system disorders and pathological conditions. In particular, NMDA receptor hypofunction may contribute significantly to the cognitive and behavioral deficits in schizophrenia. Glycine binds within the NMDA receptor and is necessary for glutamatergic activation of the receptor. Agonists that act at the glycine site of the NMDA receptor increase receptor activity and may have therapeutic potential for treating Schizophrenia. However, relatively few drug candidates have been identified which function by this mechanism because of the difficulty in developing novel molecules that resemble glycine, retain agonist activity, and cross the blood-brain barrier. In the following application, a research program is described to identify drug candidates that increase synaptic glycine concentrations through inhibition of its removal, thereby potentiating NMDA receptor activity. Our prototype compounds, which selectively block the glycine GlyT1 transporter that acts at the NMDA synapse, provide evidence that such a strategy is feasible. Further design and synthesis of analog compounds, to be screened in our established GlyT1 and other secondary selectivity assays, is proposed in this Phase I application. Preliminary behavioral testing will establish functional outcomes and central nervous system penetration. Novel molecules that act selectively to elevate glycine levels at the NMDA receptor have considerable commercial potential for the treatment of neuropsychological disorders such as schizophrenia and possibly other cognitive and neurodegenerative disorders. PROPOSED COMMERCIAL APPLICATION: Compounds identified from this program will have the potential to treat the neuropsychological symptoms of Schizophrenia and dementia.